Neoplastic diseases, characterized by the proliferation of cells not subject to the normal control of cell growth, are a major cause of death in humans and other mammals. Clinical experience in cancer chemotherapy has demonstrated that new and more effective drugs are desirable to treat these diseases. Such clinical experience has also demonstrated that drugs which disrupt the microtubule system of the cytoskeleton can be effective in inhibiting the proliferation of neoplastic cells.
Cryptophycin compounds can now be prepared using a total synthetic process; however, many of the useful cryptophycin compounds contain a labile epoxide group. Barrow, R. A. et al., J. Am. Chem. Soc. 117, 2479 (1995). Applicants have discovered that the beta-epoxide can be particularly desired. However, in the Barrow et al. synthesis of some of the cryptophycin compounds of formula (I) below, the epoxidation is performed in the last step which provides only a 2:1 selectivity for the desired epoxide. Furthermore, the diasteromers are difficult to separate at this stage. While it would be desirable to epoxidize an earlier intermediate in the process, epoxides are sensitive to a number of reaction conditions. Moreover, there remains a need for processes with greater stereoselectivity to avoid difficult diastereomeric separations.
The present invention provides a much desired novel and efficient method for preparing cryptophycin compounds having an epoxide functionality. The epoxidation is selective and may be employed at various steps in the overall synthetic process.